Injectable non-aqueous therapeutic compositions

ABSTRACT

An injectable synergistic one-phase formulation, which comprises 10 to 50% w/v of the potentiator composition consisting of sulphadimidine and sulphathiazole in a ratio of 1 to 3, to 3 to 1, and of trimethoprim in N,N-dimethylacetamide, the ratio of the sulpha-components together to trimethoprim being from 3.5 to 1, to 7 to 1, methods for the preparation of such a formulation and for the use of the same for the treatment of animals.

This is a continuation, of application Ser. No. 508,562 filed Sept. 23, 1974, now abandoned.

The present invention relates to injectable therapeutic compositions containing sulphonamides and a sulphonamide potentiator.

It is well known that the chemotherapeutic, especially antibacterial activities of sulphonamides and of certain 2,4-diamino-pyrimidine derivatives, are mutually enhanced when these agents act together in the human or animal organism. Trimethoprim is now well established as one of the best potentiators of sulphonamides in human and veterinary medicines, and has widely been used in combination with sulphamethoxazole, sulphadiazine and sulphadoxine.

Whilst such preparations are frequently administered orally, there is also a need for injectable formulations which are sufficiently concentrated for convenient use and are highly active against various infections. This problem of the size of the injectable solution containing an effective dosage of the potentiated combination, is particularly important when the treatment of large domestic animals arises in veterinary practice.

It is not possible to keep both the sulphonamide and the trimethoprim components in aqueous solution simultaneously since the former provides soluble salts only with certain bases whilst the basically reacting potentiators give suitable soluble salts only with certain acids. The mixing of such aqueous solutions of the components inevitably results in precipitation, which makes manufacture of injectable solutions in this manner impossible.

Various attempts have been made to overcome the difficulties and formulate these medicaments for injection. According to British Patent Specification 1,176,395 (or DGS 1,617,521), the sulphonamide is prepared in an aqueous solution as a salt and the potentiator in a water-miscible organic solvent before the two solutions are combined. The use of the alkali metal salts represents highly basic conditions, but when the pH is adjusted to provide milder conditions insoluble complexes of the sulphonamide, e.g. sulphamethoxazole with trimethoprim, are formed. In addition, any provision of concentrations substantially higher than 20%, requires the increase of the sulphonamide relative to the potentiator, which results in a medically less advantageous formulation.

Highly concentrated aqueous systems, which could nevertheless maintain the often optimum 5 to 1 ratio of these two types of components, were suggested in the prior art. The preparation of such systems involved the use of a finely dispersed suspension of the potentiator in an alkaline solution of the sulphonamide. Although this represents a satisfactory preparation for the purpose of treatment in many cases, the two-phase character of the formulation constitutes a departure from ideal of a clear solution, which is preferred for injection in many instances and is essential for intravenous administration.

It has now been found that a one-phase formulation of a combination of trimethoprim with two selected sulphonamides, namely sulphadimidine and sulphathiazole, can be achieved at a high concentration without resorting to any use of inorganic salt-forming agents. The solvent required for this purpose is N,N-dimethylacetamide, which enables the complete ommission of solubilising, stabilising and preservative agents often required to prevent crystallisation or decomposition of the ingredients at normal or low temperatures. Under the conditions required by the invention the concentration of the active ingredients can be 45% or even higher, without the necessity of distorting the optimum ratios of the potentiator to the sulphonamide, or rendering the physical properties of the solution unsuitable for injections.

According to the present invention in one aspect therefore there is provided an injectable one-phase formulation, which comprises 10 to 50% w/v of the potentiator composition consisting of sulphadimidine and sulphathiazole in a ratio of 1 to 3, to 3 to 1, preferably around 1 to 1, and of trimethoprim in N,N-dimethylacetamide, the ratio of the sulphacomponents together to trimethoprim being from 3.5 to 1, to 7 to 1, preferably around 5 to 1.

Since the formulation according to the invention is using a completely non-aqueous system, and the components are dissolved in their free form as weak acids and basis, respectively, the overall reaction of the solution can be assumed to be neutral relative to the body fluids of the injected species. In the absence of substantial excesses of alkaline salt forming agents characteristic of prior formulations, trimethoprim may perhaps be absorbed more readily from the site of injection than before. No undesirable or abnormal side effects or local reactions were observed in the use and the formulation was found safe and efficacious for the treatment of animals suffering from a variety of bacterial infections. The small size of the vaccine, around 20ml. for 400 to 600 Kg. body weight, is particularly convenient when horses are injected intramascularly in view of the well know sensitivity of these animals to intramuscular treatment.

The trimethoprim component can be advantageiously prepared for incorporation in the formulations according to the present invention by reacting guanidine with a compound of general formula (I). ##STR1##

When X and Y taken together represent an additional bond, Z represents either:

(i) the group NR⁴ R⁵ which is an aliphatic, heterocyclic, or aromatic amino group, preferably an anilino or morpholino group, wherein R⁴ and R⁵ cannot both be hydrogen, suitable process conditions for the reaction with guanidine being those described in Belgian Patent Specification No. 746,846 or United States Patent Application No. 16606 filed Mar. 4, 1970 now U.S. Pat. No. 3,697,512; or

(ii) an alkoxy, preferably a methoxy, or thioalkyl group, suitable process conditions for the reaction with guanidine being those described in, for example, United Kingdom Patent Specification No. 957,797.

When X represents a hydrogen atom Y and Z each represent an alkoxy group, preferably a methoxy group, or taken together represent an alkylene dioxy group. That is, when X represents a hydrogen atom, the -CHYZ moiety represents a dialkyl or an alkylene acetal group, preferably a dimethyl acetal group. It will be appreciated that the dialkyl acetal group has an acyclic structure while the alkylene acetal group has a cyclic structure. Suitable process conditions for the reaction with guanidine being those described in, for example, United Kingdom Patent Specification Nos. 1,142,654 or 1,102,142.

The reaction with guanidine may be conveniently effected in a lower alkanol solvent, for example, methanol, ethanol or It is particularly preferred that the reaction be carried out at the reflux temperature of the reaction mixture but useful reaction rates have been obtained at temperatures down to room temperature. It has been found that the reaction with guanidine of compounds of formula (II) wherein X and Y together represent an additional bond and Z represents the group NR⁴ R⁵ can also be effected if the guanidine is in the form of the carbonate in a polar aprotic solvent, e.g., dimethyl sulphoxide or hexamethyl phosphoramide. The guanidine is, however, normally utilised in the form of the salt of a strong acid, such as the hydrochloride, in the presence of at least an equivalent of a base sufficient to liberate the guanidine.

The trimethoprim prepared in this manner may then be isolated, and purified, if necessary, for incorporation in the injectable formulation.

The use of a combination of two sulphonamides contributes to the stability of the solution, and is also advantageous from the clinical point of view. The antibacterial efficacy of the equimolar mixtures of sulphadimidine and sulphathiazole is superior to that of sulphadiazine in many instances, and the solubilities of these agents are higher than that of sulphadiazine both in acid and alkaline media. This is important from the point of view of kidney compatibility and is advantageous when the product is administered to newly born piglets or patients with kidney damage.

The relative proportions of the sulphadimidine and sulphathiazole can be varied as suggested above, although it is preferred to use them in about equal amounts. The ratio of the sulpha-components to trimethoprim may also be adjusted within the suggested limits to suit the requirements of the treated animals and the nature of the disease. It appears that a 5 to 1 ratio is clinically optimum and convenient in many instances.

Formulations according to the invention can be easily prepared by dissolving for instance first the sulpha components in the solvent and adding trimethoprim afterwards. For certain purposes N,N-diethylacetamide can replace partially or fully the required adjusted N,N-dimethylacetamide without any appreciable difference. The volume of the formulation may be finally adjusted by the addition of further amounts of acetamide or small amounts of other non-aqueous solvents. The amounts of the potentiated composition can conveniently vary within the formulation from 10 to 50%, preferably from 20 to 48% w/v. For larger animals the concentration may be adjusted to say 48%, whilst middle size animals or calves are preferably injected with 24% solutions. The composition may also contain other ingredients, such as anti-histamines, vitamins or corticosteroids.

Effective dosages for the treatment of cattle or horses may conveniently contain 1.6g. of trimethoprim and 8.0g. of equimolar sulphadimidine and sulphathiazole in a 20ml. solution. More diluted versions containing 2.4g. of total ingredients in 10ml. are recommended for middle-size animals, such as pigs or calves, and smaller dosages of the same formulation 1ml, may be eminently suitable for small domestic animals.

The bulk of the solution prepared on a large scale may be easily sterilised by filtration for instance through Seitz-filters, (e.g. 10-2 type in K 7 layers) under pressure. The solution so obtained can be distributed into sterile ampoules as required.

According to the present invention in another aspect, there is provided a method for the treatment of animals and human patients, which comprises the administration of an effective dosage of a formulation, as hereinbefore defined. In particular from 16mg./Kg. to 24mg./Kg, preferably around 20mg./Kg, can be administered by the intramuscular or intravenous route.

EXAMPLE 1

N,N-dimethylacetamide (6 liters) was transferred into a 10-liter flask and allowed to stand for 10 minutes under a stream of nitrogen gas. Sulphadimidine (2kg) was added into the solvent and dissolved whilst continuing the introduction of nitrogen gas flow. As soon as clear solution was achieved sulphathiazole (2kg) was added and brought into solution under similar conditions at room temperature before trimethoprim (800g) was treated in the same manner.

The completed solution containing all three active ingredients was adjusted to the required final volume (10 liter) with N,N-dimethylacetamide. The 48% w/v solution was then sterilised by filtration through a 10-2 Seitz filter (K 7 layers) under a nitrogen pressure (0.9 atu). The liquid preparation was distributed into 100ml-flasks under sterile conditions and nitrogen gas. The bottled product was tested for sterility and other requirements, and used in field trials in cattle and horses with satisfactory results.

EXAMPLE 2

The solution containing 48% of the combination product was prepared according to the method of Example 1 and diluted to a strength of 24% w/v. The bottled and tested sterile preparation was then employed for the treatment of calves and pigs in dosages of 10ml. for 100-150 body weight, with satisfactory results. 

What we claim is:
 1. An injectable non-aqueous one-phase formulation for treating bacterial infections in animals and humans which comprises from 10 to 50% w/v of a potentiated composition consisting of sulphadimidine and sulphathiazole in a ratio of from 1:3 to 3:1, and trimethoprim in a ratio to the combined sulpha-component of from 3.5:1 to 7:1 the composition being dissolved in N,N-dimethylacetamide.
 2. A formulation according to claim 1, wherein the ratio of sulphadimidine to sulphathiazole is around 1:1.
 3. A formulation according to claim 2, wherein the ratio of sulphonamides together to trimethoprim is around 5:1.
 4. A formulation according to claim 3, wherein the total concentration of therapeutically active ingredients is higher than 45% w/v.
 5. A formulation according to claim 4, wherein the total concentration is 48% w/v.
 6. A method of treating bacterial infections in animals and humans having a bacterial infection comprising the intramuscular or intravenous administration to said animal or human of an effective antibacterial dose of 16 to 24 mg/kg of the formulation of claim
 1. 7. A method according to claim 6, wherein 20 ml of a 48% w/v formulation is injected intramuscularly or intravenously into cattle or horses.
 8. A method according to claim 6, wherein 10 ml of a 24% w/v formulation is injected intramuscularly or intravenously into pigs or calves. 